The planned research addresses a problem of fundamental importance to the neuroscience community - brain delivery. While some studies suggest that bioengineered reagents can reach the brain when delivered into the systemic vasculature, the complex nature of these previously developed reagents makes implementation for science unwieldy, and adaptation as a therapeutic medicine unlikely. Only a handful of laboratories are capable of generating and using these complex reagents, and for most cases, there has been little progress towards translation to therapies despite more than 10 years of engineering and testing in animal models. We propose that new methods merging chemical simplicity with the power of in vivo selection can solve this monumental problem. In this proposal, we will test the feasibility of developing RNA aptamers capable of directing a payload to neurons, astrocytes, or brain endothelia cells. PUBLIC HEALTH RELEVANCE: This EUREKA proposal addresses a problem of fundamental importance to the scientific and medical community - getting material into the brain without directly injecting it into the brain. Some earlier work made a complex of materials that could deliver a gene of interest or a small peptide to the brain. But these studies were done more than a decade ago and yet this approach is still not used widely. This is probably because it is very labor intensive to make these complex materials. Also, because the systems currently used have many components, it is not likely to be developed into a drug. To get around this problem, we propose to use a very simple molecule, RNA. We can generate 10^12 different RNAs that naturally fold into various structures. Interestingly, these structures are capable of binding to a variety of cell surface proteins or other cell surface material. In our preliminary work, we found that delivery of some of these RNAs into the tail vein of the mouse could reach the brain. What we propose here is to develop more aptamers, and test their ability to reach different types of brain cells following delivery into the mouse tail vein. If we are successful, we would have made an enormous leap in the biosciences. Our data will be of exceptional importance and find broad use in the scientific community. [unreadable] [unreadable] [unreadable]